Cutaneous Manifestations of Biological Warfare and Related Threat Agents

McGovern, Thomas W.; Christopher, George W.; Eitzen, Edward M.

doi:10.1001/archderm.135.3.311

Cited by 51 publications

(38 citation statements)

References 62 publications

(105 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Despite efforts to eradicate the disease, it has recently been recognized by the World Health Organization as a re-emerging public health concern. In addition, there is increasing risk of misuse of infectious agents, such as Y. pestis, as weapons of terror as well as instruments of warfare for mass destruction (7). Thus, there is an urgent need to devise effective protective strategies that could be implemented soon after a bioterrorist attack.…”

mentioning

confidence: 99%

Crystal Structure of the Yersinia Protein-tyrosine Phosphatase YopH Complexed with a Specific Small Molecule Inhibitor

Sun

Fedorov

et al. 2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

The pathogenic bacteria Yersinia are causative agents in human diseases ranging from gastrointestinal syndromes to bubonic plague. There is increasing risk of misuse of infectious agents, such as Yersinia pestis, as weapons of terror as well as instruments of warfare for mass destruction. Because the phosphatase activity of the Yersinia protein tyrosine phosphatase, YopH, is essential for virulence in the Yersinia pathogen, potent and selective YopH inhibitors are expected to serve as novel anti-plague agents. We have identified a specific YopH small molecule inhibitor, p-nitrocatechol sulfate (pNCS), which exhibits a K i value of 25 M for YopH and displays a 13-60-fold selectivity in favor of YopH against a panel of mammalian PTPs. To facilitate the understanding of the underlying molecular basis for tight binding and specificity, we have determined the crystal structure of YopH in complex with pNCS at a 2.0-Å resolution. The structural data are corroborated by results from kinetic analyses of the interactions of YopH and its site-directed mutants with pNCS. The results show that while the interactions of the sulfuryl moiety and the phenyl ring with the YopH active site contribute to pNCS binding affinity, additional interactions of the hydroxyl and nitro groups in pNCS with Asp-356, Gln-357, Arg-404, and Gln-446 are responsible for the increased potency and selectivity. In particular, we note that residues Arg-404, Glu-290, Asp-356, and a bound water (WAT185) participate in a unique H-bonding network with the hydroxyl group ortho to the sulfuryl moiety, which may be exploited to design more potent and specific YopH inhibitors. Protein tyrosine phosphatases (PTPs)1 are involved in the regulation of numerous cell functions including growth, differentiation, motility, cell-cell interactions, metabolism, gene transcription, and the immune response (1, 2). In vivo, tyrosine phosphorylation is a reversible and dynamic process. The phosphorylation states of proteins are governed by the opposing actions of protein tyrosine kinases, which catalyze protein tyrosine phosphorylation, and PTPs, which are responsible for dephosphorylation. Hundreds of protein kinases and protein phosphatases and their substrates are integrated within an elaborate signal-transducing network. The defective or inappropriate operation of this network is at the root of such widespread diseases including cancers and diabetes.

show abstract

mentioning

confidence: 99%

Crystal Structure of the Yersinia Protein-tyrosine Phosphatase YopH Complexed with a Specific Small Molecule Inhibitor

Sun

Fedorov

et al. 2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Preliminary BLAST (4) comparisons indicate that the genes conserved between these species are ϳ99% identical at the nucleotide level. This high level of nucleotide identity makes it challenging to use nucleic acid-based assays to discriminate between B. mallei and B. pseudomallei (6, 71).There are legitimate concerns that B. mallei and B. pseudomallei may be misused as biological weapons (16,46,51,60), and there is compelling evidence that B. mallei has already been used in this manner (3, 74). Diagnostic assays should be developed to discriminate between these microorganisms in the event that they are misused in the future.…”

mentioning

confidence: 99%

Burkholderia thailandensis E125 Harbors a Temperate Bacteriophage Specific for Burkholderia mallei

et al. 2002

View full text Add to dashboard Cite

Burkholderia thailandensis is a nonpathogenic gram-negative bacillus that is closely related to Burkholderia mallei and Burkholderia pseudomallei. We found that B. thailandensis E125 spontaneously produced a bacteriophage, termed E125, which formed turbid plaques in top agar containing B. mallei ATCC 23344. We examined the host range of E125 and found that it formed plaques on B. mallei but not on any other bacterial species tested, including B. thailandensis and B. pseudomallei. Examination of the bacteriophage by transmission electron microscopy revealed an isometric head and a long noncontractile tail. B. mallei NCTC 120 and B. mallei DB110795 were resistant to infection with E125 and did not produce lipopolysaccharide (LPS) O antigen due to IS407A insertions in wbiE and wbiG, respectively. wbiE was provided in trans on a broad-hostrange plasmid to B. mallei NCTC 120, and it restored LPS O-antigen production and susceptibility to E125. The 53,373-bp E125 genome contained 70 genes, an IS3 family insertion sequence (ISBt3), and an attachment site (attP) encompassing the 3 end of a proline tRNA (UGG) gene. While the overall genetic organization of the E125 genome was similar to -like bacteriophages and prophages, it also possessed a novel cluster of putative replication and lysogeny genes. The E125 genome encoded an adenine and a cytosine methyltransferase, and purified bacteriophage DNA contained both N6-methyladenine and N4-methylcytosine. The results presented here demonstrate that E125 is a new member of the supergroup of Siphoviridae that may be useful as a diagnostic tool for B. mallei.The disease glanders is caused by Burkholderia mallei, a host-adapted pathogen that does not persist in nature outside of its horse host (32). Glanders is a zoonosis, and humans whose occupations put them into close contact with infected animals can contract the disease. There have been no naturally occurring cases of glanders in North America in the last 60 years, but laboratory workers are still at risk of infection with B. mallei via cutaneous (68) and inhalational (31) routes. Human glanders has been described as a painful and loathsome disease from which few recover without antibiotic intervention (33, 51). There is little known about the virulence factors of this organism, but a recent report indicates that the capsular polysaccharide is essential for virulence in hamsters and mice (24).Burkholderia pseudomallei is the etiologic agent of the glanders-like disease melioidosis (21). As the names suggest, B. mallei and B. pseudomallei are closely related species (19,56,59,69). These ␤-Proteobacteria can now be directly compared at the genomic level because the B. pseudomallei K96243 genomic sequence is available at the Sanger Institute website (http://www.sanger.ac.uk/) and the B. mallei ATCC 23344 genomic sequence is available at the TIGR (The Institute for Genomic Research) website (http://www.tigr.org/). Preliminary BLAST (4) comparisons indicate that the genes conserved between these species are ϳ99% identical at the ...

show abstract

“…A key factor in the accurate diagnosis and appropriate management of waterborne disease resulting from water terrorism is inclusion of water by medical and public health practitioners as one possible exposure pathway of biowarfare agents at the time of initial case presentation. The biological agents and biotoxins that have been designated as potential bioterrorist weapons arise from varied biological compounds and can be dispersed through multiple exposure pathways including water (7,23,28,30,35,39,42,44).…”

Section: Intentional Dispersal Of Bioweapons Using Multiple Exposure mentioning

confidence: 99%

“…Several published epidemiologic patterns and clinical sentinel clues provide a valuable resource for both the medical and public health community facing the challenges of diagnosing terrorism-related illness and injury (8,11,23,34,38,44,48,51). These epidemiologic indicators may result from multiple exposure pathways including water and have universal application in a clinical and public health setting (see Table 3).…”

Section: Use Of Diagnostic Indicators and Epidemiologic Patterns To Dmentioning

confidence: 99%

“…Increased and early presentation of immunocompromised patients and vulnerable population patients with debilitating disease because the dose of inoculum or biotoxic exposure required to cause disease may be less than for the general healthy population "Impossible epidemiology" with naturally occurring diseases diagnosed in geographic regions where the disease has not been encountered previously Unusual or uncommon route of exposure of a disease such as illness resulting from a waterborne agent not normally found in the water environment a Several epidemiologic patterns are presented above that have been identified as possible sentinel clues of a terrorist attack from several public health and military sources (8,11,23,34,38,44,48,51). None of these indicators alone is pathognomonic for terrorism-related disease, but they are presented as an educational tool for use by health care providers and public health practitioners as possible disease trends that may warrant further investigation.…”

Section: Use Of Syndromic Surveillance and Disease Trends To Assist Imentioning

confidence: 99%

See 1 more Smart Citation

WATER AND BIOTERRORISM: Preparing for the Potential Threat to U.S. Water Supplies and Public Health

Meinhardt

2005

Annu. Rev. Public Health

View full text Add to dashboard Cite

Key Words water terrorism, waterborne disease, intentional water contamination, biowarfare agents, biotoxins ■ Abstract Water supplies and water distribution systems represent potential targets for terrorist activity in the United States because of the critical need for water in every sector of our industrialized society. Even short-term disruption of water service can significantly impact a community, and intentional contamination of a municipal water system as part of a terrorist attack could lead to serious medical, public health, and economic consequences. Most practicing physicians and public health professionals in the United States have received limited training in the recognition and evaluation of waterborne disease from either natural or intentional contamination of water. Therefore, they are poorly prepared to detect water-related disease resulting from intentional contamination and may not be adequately trained to respond appropriately to a terrorist assault on water. The purpose of this review is to address this critical information gap and present relevant epidemiologic and clinical information for public health and medical practitioners who may be faced with addressing the recognition, management, and prevention of water terrorism in their communities.

show abstract

Cutaneous Manifestations of Biological Warfare and Related Threat Agents

Cited by 51 publications

References 62 publications

Crystal Structure of the Yersinia Protein-tyrosine Phosphatase YopH Complexed with a Specific Small Molecule Inhibitor

Crystal Structure of the Yersinia Protein-tyrosine Phosphatase YopH Complexed with a Specific Small Molecule Inhibitor

Burkholderia thailandensis E125 Harbors a Temperate Bacteriophage Specific for Burkholderia mallei

WATER AND BIOTERRORISM: Preparing for the Potential Threat to U.S. Water Supplies and Public Health

Contact Info

Product

Resources

About